The present invention relates to an improved method of making 2,7-dimethyl-2,4,6-octatrienedial and related derivatives. Specifically, this invention describes a method for reacting a readily available four carbon atom bisphosphonate with two equivalents of both a pyruvic aldehyde derivative and a powdered alkali metal hydroxide to give the desired dimethyloctatrienedial in high yields.
The group of naturally occurring compounds commonly known as carotenoids have found increasing uses in the coloration of foodstuffs and in animal feedstocks. The carotenoids include terpenes made of forty carbon atoms. For example, beta-carotene, illustrated by Formula I, is a representative compound of this class. ##STR1##
Published syntheses of beta-carotene have advantageously used the symmetry of the compound to develop convergent synthetic schemes to make the compound. In particular, the ten carbon atom fragment in the center of the compound (the fragment included within the dashed lines as illustrated in Formula I) has been used in known synthetic schemes. Various methods for preparing this ten carbon atom fragment are described by Isler, Carotenoids, Birkhauser-Verlag, 431-436 (1971) and by Pommer et al, "Industrial Applications of the Wittig Reaction," Topics in Current Chemistry, 109: 165-188 (1983).
A known industrial preparation of the ten carbon fragment 2,7-dimethyl-2,4,6-octatrienedial was developed by BASF. The BASF process described by Pommer, Angew. Chem., 72: 911-915 (1960) is schematically outlined in Scheme 1: ##STR2##
This sequence has also been described in German Patent 1,092,472, Nov. 10, 1960. The abstract of this patent in Chemical Abstracts, 56: 413d (1962) describes the reaction conditions used for the sequence illustrated in Scheme 1 as reacting the bisphosphonate with an excess of the carbonyl compound in the solvent dimethylformamide in the presence of sodium methoxide. As reported, the reaction of the bisphosphonate (53 g) with an excess of the diethoxy pyruvaldehyde derivative (88 g) gave the desired octatrienedial (14.7 g), a yield of about 55%. The overall low efficiency of this reported sequence, use of a less desirable solvent, and use of an excess of the protected aldehyde reagent indicate a need for a more efficient process employing reagents and solvents which are easier to handle, dispose of and recycle when used in a larger scale process.
The undesirable, low yields associated with the reaction of carbonyl compounds with this same bisphosphonate reagent are described by Carsky et al., Liebig's Annalen der Chemie, 291-304 (1980). Reported yields of the reactions of various carbonyl compounds with this bisphosphonate were generally low ranging from about 20-25%. The described reaction conditions reacted the bisphosphonate with the carbonyl compounds in 1,2-dimethoxyethane in the presence of potassium tert-butoxide. The generally low yields provided by these conditions suggest that using aprotic solvents and alkoxide bases does not provide an efficient, economical synthetic route to 2,7-dimethyl-2,4,6-octatrienedial. Attempts to duplicate similar methods also were found to be unsatisfactory due to poor yields and/or complex reaction mixtures which may require potentially costly and complex purification schemes if used in large-scale commercial preparations.
The present invention provides for the formation of 2,7-dimethyl-2,4,6-octatrienedial using inexpensive, recyclable nonpolar solvents and an alkali metal hydroxide. It was unexpected that the use of a virtually insoluble hydroxide base in a nonpolar solvent would provide both an increase in the overall yield of the coupling reaction between the bisphosphonate and the carbonyl compound and a decrease in the formation of undesired by-products.
The observed increase in yield is certainly unpredicted because the use of a hydroxide base in nonpolar solvents generally must be performed under phase-transfer catalysis conditions. When the coupling reaction is done under phase-transfer catalysis conditions, typically use of a nonpolar solvent, saturated aqueous hydroxide and a catalytic amount of a quaternary ammonium salt, the coupling reaction was found to be less satisfactory than when powdered hydroxide alone was used. It was also observed that the use of an alkoxide base, which is a more soluble base in nonpolar solvents, was less satisfactory than use of powdered hydroxide alone. The unpredicted increased overall yield and decreased formation of by-products provided by the present method is an important feature of this invention.